The Endoplasmic Reticulum–Plasma Membrane Junction: A Hub for Agonist Regulation of Ca²⁺ Entry

Abstract

Stimulation of cell-surface receptors induces cytosolic Ca²⁺ ([Ca²⁺]_i) increases that are detected and transduced by effector proteins for regulation of cell function. Intracellular Ca²⁺ release, via endoplasmic reticulum (ER) proteins inositol 1,4,5-trisphosphate receptors (IP₃R) and ryanodine receptors (RyR), and Ca²⁺ influx, via store-operated Ca²⁺ entry (SOCE), contribute to the increase in [Ca²⁺]_i. The amplitude, frequency, and spatial characteristics of the [Ca²⁺]_i increases are controlled by the compartmentalization of proteins into signaling complexes such as receptor-signaling complexes and SOCE complexes. Both complexes include protein and lipid components, located in the plasma membrane (PM) and ER. Receptor signaling initiates in the PM via phospholipase C (PLC)-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP₂), and culminates with the activation of IP₃R in the ER. Conversely, SOCE is initiated in the ER by Ca²⁺-sensing stromal interaction molecule (STIM) proteins, which then interact with PM channels Orai1 and TRPC1 to activate Ca²⁺ entry. This review will address how ER–PM junctions serve a central role in agonist regulation of SOCE.